A TAS1R receptor-based explanation of sweet ‘water-taste’

Miraculin (MCL) is a homodimeric protein isolated from the red berries of Richadella dulcifica. MCL, although flat in taste at neutral pH, has taste-modifying activity to convert sour stimuli to sweetness. Once MCL is held on the tongue, strong sweetness is sensed over 1 h each time we taste a sour solution. Nevertheless, no molecular mechanism underlying the taste-modifying activity has been clarified. In this study, we succeeded in quantitatively evaluating the acid-induced sweetness of MCL using a cell-based assay system and found that MCL activated hT1R2-hT1R3 pHdependently as the pH decreased from 6.5 to 4.8, and that the receptor activation occurred every time an acid solution was applied. Although MCL per se is sensory-inactive at pH 6.7 or higher, it suppressed the response of hT1R2-hT1R3 to other sweeteners at neutral pH and enhanced the response at weakly acidic pH. Using human/mouse chimeric receptors and molecular modeling, we revealed that the amino-terminal domain of hT1R2 is required for the response to MCL. Our data suggest that MCL binds hT1R2-hT1R3 as an antagonist at neutral pH and functionally changes into an agonist at acidic pH, and we conclude this may cause its taste-modifying activity.G protein-coupled receptor | positive allosteric modulator | taste-modifying protein | calcium imaging

Section: Discussionmentioning

confidence: 93%

Human sweet taste receptor mediates acid-induced sweetness of miraculin

Koizumi¹,

Tsuchiya²,

Nakajima³

et al. 2011

“…In contrast, hits that interact with the TMD of sweet taste receptor are agonists (10,18). This could be due to the significant level of constitutive activity of the sweet taste receptor (31), which would enable the active molecules interacting within the TMD to elicit a significant agonist activity and perceptible level of sweet taste (17). A continuing research and screening effort should allow us to discover additional selective enhancers ] int was monitored.…”

Section: Resultsmentioning

confidence: 99%

Positive allosteric modulators of the human sweet taste receptor enhance sweet taste

Servant¹,

Tachdjian²,

Tang³

et al. 2010

119

To identify molecules that could enhance sweetness perception, we undertook the screening of a compound library using a cellbased assay for the human sweet taste receptor and a panel of selected sweeteners. In one of these screens we found a hit, SE-1, which significantly enhanced the activity of sucralose in the assay. At 50 μM, SE-1 increased the sucralose potency by >20-fold. On the other hand, SE-1 exhibited little or no agonist activity on its own. SE-1 effects were strikingly selective for sucralose. Other popular sweeteners such as aspartame, cyclamate, and saccharin were not enhanced by SE-1 whereas sucrose and neotame potency were increased only by 1.3-to 2.5-fold at 50 μM. Further assayguided chemical optimization of the initial hit SE-1 led to the discovery of SE-2 and SE-3, selective enhancers of sucralose and sucrose, respectively. SE-2 (50 μM) and SE-3 (200 μM) increased sucralose and sucrose potencies in the assay by 24-and 4.7-fold, respectively. In human taste tests, 100 μM of SE-1 and SE-2 allowed for a reduction of 50% to >80% in the concentration of sucralose, respectively, while maintaining the sweetness intensity, and 100 μM SE-3 allowed for a reduction of 33% in the concentration of sucrose while maintaining the sweetness intensity. These enhancers did not exhibit any sweetness when tasted on their own. Positive allosteric modulators of the human sweet taste receptor could help reduce the caloric content in food and beverages while maintaining the desired taste.enhancer | sweetness | perception | sucrose T he steady increase of the daily consumption of dietary sugar over the last decades may have contributed to the obesity crisis and the early onset of type-II diabetes observed in many developed countries (1, 2). As a result, food and beverage companies have launched a plethora of diet brands where sugar has been partly or fully replaced by noncaloric sweeteners to decrease caloric intake. Currently some of the commonly used noncaloric sweeteners include saccharin, aspartame, cyclamate, sucralose, and acesulfame K (3, 4). However, none of these substances can completely reproduce the taste of sugar. These sweeteners all suffer from one or more shortcomings including a bitter or metallic aftertaste at high concentrations, limiting their use to lower concentrations, or temporal issues such as a delayed sweet taste onset, a lingering sweet aftertaste, or a limited maximum sweetness intensity (4, 5). Another appealing approach to address the problem, in addition to looking for novel noncaloric sweeteners, would be to find molecules capable of enhancing sweetness perception. Ideally, such an enhancer molecule would not elicit sweetness on its own but it would boost the sweetness intensity of a lower amount of sweetener or sugar. Such enhancers could therefore allow for a reduction in the amount of sugar, and calories, in food and beverages while maintaining the desired taste. Similarly, a sweet taste enhancer could allow for a reduction in the amount of noncaloric sweeteners used in "0"-calorie...

“…Perhaps the pharmacological block of TAS1R3 with clofibrate is incomplete due to poor penetration through the blood-testis barrier or by the relatively short half-life of clofibric acid. In addition, clofibric acid acts as an inverse agonist on the TAS1R3 receptor (10,52,53), and therefore, the receptor may display rebound activation after the inhibitor is removed (10,54). Thus, it is possible that during treatment of the animal, the receptor alternated between the inhibited and activated state.…”

Section: Discussionmentioning

confidence: 99%

Genetic loss or pharmacological blockade of testes-expressed taste genes causes male sterility

Mosinger

Redding

Parker

et al. 2013

TAS1R taste receptors and their associated heterotrimeric G protein gustducin are involved in sugar and amino acid sensing in taste cells and in the gastrointestinal tract. They are also strongly expressed in testis and sperm, but their functions in these tissues were previously unknown. Using mouse models, we show that the genetic absence of both TAS1R3, a component of sweet and amino acid taste receptors, and the gustducin α-subunit GNAT3 leads to malespecific sterility. To gain further insight into this effect, we generated a mouse model that expressed a humanized form of TAS1R3 susceptible to inhibition by the antilipid medication clofibrate. Sperm formation in animals without functional TAS1R3 and GNAT3 is compromised, with malformed and immotile sperm. Furthermore, clofibrate inhibition of humanized TAS1R3 in the genetic background of Tas1r3 −/− , Gnat3 −/− doubly null mice led to inducible male sterility. These results indicate a crucial role for these extraoral "taste" molecules in sperm development and maturation. We previously reported that blocking of human TAS1R3, but not mouse TAS1R3, can be achieved by common medications or chemicals in the environment. We hypothesize that even low levels of these compounds can lower sperm count and negatively affect human male fertility, which common mouse toxicology assays would not reveal. Conversely, we speculate that TAS1R3 and GNAT3 activators may help infertile men, particularly those that are affected by some of the mentioned inhibitors and/or are diagnosed with idiopathic infertility involving signaling pathway of these receptors.phenoxy compounds | spermiogenesis